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Study Rundown:

Through a novel mechanism of decreased LDL-receptor recycling and increased LDL-C clearance, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have demonstrated powerful and synergistic reductions in LDL-C in conjunction with statin therapy. Yet, no large scale studies have evaluated the efficacy of PCSK9 inhibitors in the prevention of cardiovascular outcomes. This trial evaluated the efficacy of evolocumab, a fully human monoclonal antibody against PCSK9, in reducing cardiovascular outcomes in patients on optimal statin therapy. A significant reduction was found in both the primary (a composite of death, MI, stroke, unstable angina hospitalization, and coronary revascularization) and secondary (death, MI, or stroke) endpoints without an associated increase in adverse events. However, no reduction in cardiovascular or all-cause mortality was found in the analysis of individual outcomes. Given the high cost and unclear mortality benefit, the use of PCSK9 inhibitors will likely remain relegated to select high-risk patients.

This was a parallel, double-blinded trial that enrolled a large number of patients with stable atherosclerotic cardiovascular disease and provided the first evidence for the clinical value of PCSK9 inhibitors. While no direct reduction in all-cause death was found, the data supports both the benefit of reducing LDL-C to unprecedented low levels. The major limitation of this study was the short duration of follow-up.

In-Depth [randomized controlled trial]:

This multinational study randomized 27,564 patients with established cardiovascular atherosclerotic disease to treatment with evolocumab (n = 13,784) or matching placebo (n = 13,780) in a 1:1 ratio. All patients had LDL-C of 70 mg/dL (median 92 mg/dL) or non-HDL-C levels of 100 mg/dL and were on high-intensity (69.3%) or moderate-intensity (30.4%) statin therapy at baseline. Median duration of follow-up was 26 months. The primary end point was major cardiovascular events, defined as the composite of cardiovascular death, MI, stroke, unstable angina hospitalization, or coronary revascularization. The secondary end point was the composite of cardiovascular death, MI, or stroke. Adverse events were collected to assess safety.

At 48 weeks, the mean reduction in LDL-C with evolocumab compared to placebo was 59% (95%CI 58 to 60; p < 0.001), with an absolute reduction of 56 mg/dL (95%CI 55 to 57). This reduction was sustained over time. The primary endpoint occurred in 1344 patients (9.8%) with evolocumab group compared to 1593 patients (11.3%) in placebo (HR 0.85; 95%CI, 0.79 to 0.92; p < 0.001). The risk reduction in the primary endpoint increased over time (12% in the first year to 19% beyond the first year). The secondary endpoint occurred in 816 (5.9%) with evolocumab compared to 1013 (7.4%) with placebo (HR 0.80; 95%CI 0.73 to 0.88; p < 0.001). Regarding individual outcomes, there was a 21 to 27% risk reduction in MI, stroke, and coronary revascularization. No significant difference in cardiovascular or all-cause mortality was reported. All data was consistent across major demographic subgroups and quartiles of baseline LDL-C levels. Except for mild injection site reactions (2.1% vs. 1.6% with placebo), no significant difference in adverse events – including new-onset diabetes, antibody development, or neurocognitive adverse events – were associated with evolocumab.